Parkinson's disease (PD) is the second most common neurodegenerative disease and affects 1-2% elderly people above the age of 65 while one-tenth of patients are diagnosed at the age around 50 worldwide1. The etiology of PD is still not clear, but it's believed that oxidative injury causes the loss of dopamine-secreting neurons in substantia nigra, and subsequent symptoms including tremor, stiffness and movement disorders2. L-DOPA, dopamine agonists, MAO-B inhibitors and NMDA receptor antagonists have been recently evaluated to ameliorate the motor symptoms in PD patients3, 4. None of the current therapies is clinically proven for halting progression of neurodegeneration5. On the other hand, neurogenesis is often impaired in aging brains, PD and other neurodegenerative disorders due to the insufficient production of neurotrophic factors6. Interestingly, neurogenesis is also reduced in 6-hydroxydopamine (6-OHDA)-induced PD animal models and transgenic mice that overproduce human α-synuclein7. In fact, neurotrophic factor therapies have been evaluated to enhance neurogenesis for the treatment of PD and Alzheimer's disease8. However, the clinical applications of NGF and several other neurotrophic factors have been dampened by the delivery issues and side effects9. Thus, enormous effort has been made to search for small molecules to mimic or enhance the pharmacological effects of neurotrophic factors on neuroprotection and neuroregeneration.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important intracellular redox-sensitive transcription factor10, 11. The Keap1-Nrf2-ARE pathway regulates the cellular defense mechanisms against oxidative stress. The Keap1-Nrf2-ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related diseases including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Importantly, various electrophilic inducers disassociate the Nrf2-Keap1 complex via covalently modifying Keap112, 13. Consequently, Nrf2 is translocated into the cell nucleus and activates the expression of various phase II defense enzymes, antioxidant proteins and anti-inflammatory factors10, 11. As an example, heme oxygenase-1 (HO-1) is induced by Nrf2-mediated mechanism. HO-1 catalyzes the degradation of pro-oxidant heme to biliverdin/bilirubin, carbon monoxide and ferrous ion. HO-1 thereby exhibits a broad range of biological activities such as antioxidant, anti-inflammatory, neuroprotective and immunomodulatory activities14, 15. Importantly, the Nrf2/HO-1 pathway also plays a key role in neurogenesis and neurite outgrowth16, 17. Therefore, the Nrf2/HO-1 pathway becomes a therapeutic target in the treatment of various neurodegenerative disorders including PD12, 15, 18.
Natural products constitute a rich resource for the identification of neuroprotectants and neuroregenerative reagents19, 20. Caffeic acid derivatives exert anti-oxidant, anti-inflammatory, chemopreventive, anticancer and antibacterial properties in a structure-dependent and cell-type-specific manner21, 22. It has recently been demonstrated that bornyl caffeate induced apoptosis in several cancer cell lines via stimulating GSH depletion, ROS formation and mitochondrial dysfunction23, 24. Nevertheless, recent studies also demonstrated that caffeic acid derivatives induced brain-derived neurotrophic factor (BDNF) expression and scavenged neurotoxic peroxynitrite25, 26. However, caffeic acid derivatives have not been investigated for neuroprotection and neuritogenesis against 6-OHDA induced neurotoxicity.